1. It is now 45 years since aldosterone was isolated and 25 years since its genomic action, via mineralocorticoid receptors (MR), was first described.
2. Although the classic physiological role of aldosterone is to promote unidirectional transepithelial sodium transport, our ignorance of the mechanisms involved remains profound.
3. Unanswered questions include: (i) the physiological significance of the equivalent, high affinity of MR for aldosterone, progesterone, corticosterone and cortisol; (ii) the protein(s) induced as a direct transcriptional response to aldosterone; (iii) the physiological roles of MR in non-epithelial tissues where aldosterone, in concert with salt loading, produces direct pathophysiological effects; (iv) how aldosterone occupies epithelial MR, despite the 100-fold 'advantage' it enjoys over cortisol/corticosterone due to transcortin binding/11β-hydroxysteroid dehydrogenase activity, as plasma glucocorticoid levels are approximately 2000-fold higher; and (v) how epithelial MR, normally overwhelmingly occupied by glucocorticoids, are not transcriptionally active under normal circumstances in vivo, in contrast with transfection systems or the syndrome of apparent mineralocorticoid excess.
4. Possible avenues for consideration of the last two of these questions are briefly proposed.